The present invention relates to novel oxazolidinone thioamides which have new piperazine amide substituents; and their preparations. These compounds have potent activities against gram positive and gram-negative bacteria.
The oxazolidlinone antibacterial agents are a novel synthetic class of antimicrobials with potent activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium.
However, oxazolidinones generally do not demonstrate an activity at a useful level against aerobic gram-negative organisms. Thus, the use of these oxazolidinone antibacterial agents is limited to infectious states due to gram-positive bacteria. Accordingly, it is among the objects of the present invention to provide pharmaceutical compounds which have broader antibacterial activity including the activity against aerobic gram-negative organisms. We have now discovered that the oxazolidinone thioawnides of the present invention increase the spectrum of activity to include gram-negative organisms such as Haemophilus influenza and Moraxella catarrhalis.
PCT International Publication WO 98/54161 discloses oxazolidinone antibacterial agents having a thiocarbonyl functionality.
PCT International Publication WO 93/23384 discloses oxazolidinones containing a substituted diazine moiety and their use as antimicrobials.
PCT International Publication WO 95/07271 discloses substituted oxazine and thiazine oxazolidinones and their use as antimicrobials.
PCT International Publication WO 99/12914 discloses antimicrobial thiourea derivatives.
The present invention provides a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein:
A is a structure i, ii, iii or iv: 
W is NHC(=S)R1, or xe2x88x92Y-het; provided that when A is a structure iv, W is not xe2x88x92Y-het;
Y is NH, O, or S;
R1 is H, NH2, NHC1-4alkyl, C1-4alkenyl, OC1-4alkyl, or SC1-4alkyl,
(CH2)nxe2x80x94C3-6cycloalkyl, or C1-4alkyl, optionally substituted with 1-3 F, 1-2 Cl or CN;
R2 and R3 are independently H, F, Cl or C1-2alkyl;
R4 is
(a) xe2x80x94C(=O)xe2x80x94CR5R6xe2x80x94Oxe2x80x94R7,
(b) xe2x80x94C(=O)xe2x80x94CH2S(O)nxe2x80x94CH3,
(c) xe2x80x94C(=O)xe2x80x94CH2xe2x80x94S(=O)(=NR8)CH3,
(d) xe2x80x94C(=S)xe2x80x94R9,
(e) xe2x80x94C(=O)xe2x80x94CH2xe2x80x94Oxe2x80x94R10,
(f) xe2x80x94C(=O)xe2x80x94(CH2)mxe2x80x94C(=O)xe2x80x94CH3,
(g) xe2x80x94C(=O)xe2x80x94(CH2OH)2xe2x80x94CH3,
(h) xe2x80x94C(=O)xe2x80x94CH2xe2x80x94CH2xe2x80x94OR14, or
(i) xe2x80x94CN;.
R5 is H;
R6 is phenyl, benzyl, CH2OH or CH2OCH3; or R5 and R6 taken together form C3-5 cycloalkyl;
R7 is H, CH3 or C1-4 alkanoyl;
R8 is H, C1-4 alkyl, C1-4 alkanoyl, xe2x80x94C(=O)NHxe2x80x94C1-4 alkyl or xe2x80x94CO2C1-4 alkyl;
R9 is C1-4 alkyl, CH2OR11, Sxe2x80x94C1-4 alkyl, OC1-4 alkyl, or NR12R13;
R10 is phenyl, xe2x80x94CO2xe2x80x94(CH2)2xe2x80x94OCH3, xe2x80x94P(=O)(OH)2, xe2x80x94C(=O)xe2x80x94NR12R13, or xe2x80x94C(=O)xe2x80x94(CH2)2xe2x80x94CO2H;
R11 is H, phenyl, benzyl, CH3 or C(=O)CH3;
R12 and R13 are independently H or C1-3 alkyl; or R12 and R13 taken together form a 5- or 6-membered saturated heterocycle, wherein said saturated heterocycle may further contain one or two additional hetero-atoms selected from a group consisting of 0, S(O)n or NR7;
R14 is H, CH3 or benzyl;
het is a C-linked five-(5) membered heteroaryl ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, or het is a C-linked six (6) membered heteroaryl ring having 1-3 nitrogen atoms; and
n is 0, 1 or 2; and m is 0 or 1.
In another aspect, the present invention also provides:
a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
a method for treating gram-positive microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and
a method for treating gram-negative microbial infections in humans or other warm-blooded animals by administering to the subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The invention may also contain novel intermediates and processes that are useful for preparing compounds of formula I.